Clinical Scenario:
A 4-month-old infant is brought to the pediatric clinic with poor feeding, generalized weakness, and failure to thrive. Examination reveals marked hypotonia, macroglossia, and cardiomegaly. Echocardiography shows hypertrophic cardiomyopathy. Serum creatine kinase is elevated. Which of the following enzyme deficiencies is responsible for this condition?
A) Acid α-glucosidase deficiency
B) Glucose-6-phosphatase deficiency
C) Lysosomal acid lipase deficiency
D) Muscle phosphorylase deficiency
E) Pyruvate kinase deficiency
Correct answer & Explanation:
Correct Answer: A) Acid α-glucosidase deficiency
Explanation: Infantile-Onset Pompe Disease
This 4-month-old infant has infantile-onset Pompe disease (glycogen storage disease type II), an autosomal recessive lysosomal storage disorder caused by deficiency of acid α-glucosidase (GAA), also known as acid maltase.
Acid α-glucosidase normally breaks down glycogen within lysosomes into glucose. When this enzyme is deficient, glycogen progressively accumulates within lysosomes, particularly in cardiac, skeletal, and respiratory muscle.
The resulting clinical picture in classic infantile Pompe disease includes:
- Generalized hypotonia and muscle weakness
- Poor feeding and failure to thrive
- Macroglossia
- Cardiomegaly
- Hypertrophic cardiomyopathy
- Elevated creatine kinase (CK)
- Progressive respiratory muscle weakness
The cardiac involvement is particularly prominent in classic infantile-onset Pompe disease, with glycogen accumulation causing marked myocardial hypertrophy and cardiomyopathy.
Why Option A is correct
A) Acid α-glucosidase deficiency — Correct
Pompe disease results from deficiency of lysosomal acid α-glucosidase (GAA).
Unlike many other glycogen storage diseases, Pompe disease is a lysosomal glycogen storage disorder. Glycogen accumulates inside lysosomes, leading to progressive muscle damage.
The classic infantile presentation is highly characteristic:
Hypotonia + macroglossia + hypertrophic cardiomyopathy + elevated CK → Pompe disease.
Diagnosis can be confirmed by demonstrating reduced GAA enzyme activity, usually in blood-based testing such as dried blood spot screening, with confirmation in leukocytes or another appropriate tissue. Molecular testing of the GAA gene can establish the diagnosis.
Treatment
The major disease-specific treatment is enzyme replacement therapy (ERT) with recombinant human acid α-glucosidase.
Treatment should be started as early as possible, because untreated classic infantile Pompe disease can progress rapidly with severe cardiac, skeletal-muscle, and respiratory involvement.
Assessment of CRIM (cross-reactive immunologic material) status is important in infantile Pompe disease because patients who do not produce endogenous GAA are at high risk of developing antibodies against enzyme replacement therapy. Immune tolerance induction may therefore be required in appropriate patients receiving ERT.
Why the other options are incorrect
B) Glucose-6-phosphatase deficiency
Glucose-6-phosphatase deficiency causes glycogen storage disease type I (von Gierke disease).
It primarily affects the liver and kidneys, producing:
- Severe fasting hypoglycemia
- Lactic acidosis
- Hyperuricemia
- Hyperlipidemia
- Hepatomegaly
- Growth impairment
It does not produce the characteristic combination of infantile hypotonia, macroglossia, and hypertrophic cardiomyopathy seen in Pompe disease.
C) Lysosomal acid lipase deficiency
Lysosomal acid lipase deficiency causes abnormal accumulation of cholesteryl esters and triglycerides.
Severe infantile disease, historically called Wolman disease, can present with:
- Hepatosplenomegaly
- Hepatic dysfunction
- Adrenal calcification
- Vomiting and diarrhea
- Failure to thrive
It is a lipid storage disorder, not a glycogen storage disorder, and does not produce the characteristic Pompe phenotype.
D) Muscle phosphorylase deficiency
Muscle phosphorylase deficiency causes McArdle disease (glycogen storage disease type V).
The defect impairs glycogen breakdown in skeletal muscle and typically causes:
- Exercise intolerance
- Muscle cramps
- Myalgia
- Episodes of rhabdomyolysis
- Elevated CK
McArdle disease usually presents later in childhood or adulthood and does not cause the severe infantile hypotonia and hypertrophic cardiomyopathy characteristic of Pompe disease.
E) Pyruvate kinase deficiency
Pyruvate kinase deficiency is a disorder of red blood cell glycolysis, causing chronic hemolytic anemia.
Typical findings include:
- Anemia
- Jaundice
- Reticulocytosis
- Splenomegaly
- Pigment gallstones
It is not a glycogen storage disorder and does not explain this infant’s cardiomyopathy and generalized muscle weakness.
High-Yield Exam Pearl
Infant with hypotonia + macroglossia + hypertrophic cardiomyopathy → think Pompe disease → acid α-glucosidase (GAA) deficiency.
Pompe disease = GSD II = lysosomal glycogen accumulation.
Treatment: early enzyme replacement therapy, with CRIM status and immune tolerance considerations in infantile-onset disease.
Quick Differentiation
| Disorder | Enzyme defect | Main clinical clue |
|---|---|---|
| Pompe disease (GSD II) | Acid α-glucosidase (GAA) | Infantile hypotonia + hypertrophic cardiomyopathy |
| Von Gierke disease (GSD I) | Glucose-6-phosphatase | Severe fasting hypoglycemia + hepatomegaly |
| Lysosomal acid lipase deficiency | Lysosomal acid lipase | Hepatosplenomegaly + lipid accumulation |
| McArdle disease (GSD V) | Muscle phosphorylase | Exercise intolerance + muscle cramps |
| Pyruvate kinase deficiency | Pyruvate kinase | Chronic hemolytic anemia |
Reference
Al-Hassnan Z, Al Hashmi N, Makhseed N, Ben Omran T, Al Jasmi F, Al Teneiji A. Expert Group Consensus on early diagnosis and management of infantile-onset Pompe disease in the Gulf Region. Orphanet J Rare Dis. 2022;17:388. doi:10.1186/s13023-022-02545-w.
You can also practice another MCQ on Metabolic Disorder presented with failure to thrive with hepatomegaly.
